Does the vaccine protect? Soldiers are vaccinated against anthrax due to the high probability of malicious infection with the spores of B. anthracis. But will the vaccine actually protect them from disease morbidity and mortality? There is no means to test the FDA-approved AVA vaccine or any other vaccine candidate directly in humans. Antibody titers, epitope specificity, and toxin neutralizing activity in vaccinated individuals show a disturbing degree of variability. In concert with our U19 immunologists, this proposal will address these issues using nonhuman primate models of anthrax that mimic human responses. In the previous funding period, we developed, characterized and validated a baboon anthrax bacteremia model that mimics late stage disease in humans after spore germination, demonstrating the critical role of sepsis toward lethality. The current proposal builds on this foundation and is based on the hypothesis that if antibodies of known specificity and neutralizing activity can prevent infection or reduce disease severity due to B.anthracis in validated baboon models, then vaccinated individuals with similar antibodies will likewise be protected. Since not everyone responds in the same way to the vaccine, this information may contribute to risk stratification of vaccinated individuals. We aim to 1) identify polyclonal and monoclonal antibodies of known epitope specificity and functionality; 2) develop and characterize pulmonary spore models in baboons; and use these to 3) test whether the characterized antibodies are protective in the nonhuman primate disease models. The approach is strong because both baboon and human humoral responses to AVA will be characterized, many antigen-specific antibodies will be screened, and the most promising will be comprehensively tested in the baboon disease models. Minimally, we will be able to identify several candidate antibodies that may be useful immediately as passive immunity adjunctive therapeutics. We have a unique opportunity to answer critical questions by combining a genetically diverse nonhuman primate model which has a proven history of mimicking human responses to anthrax challenge with novel technologies provided by the immunologists on this U19 grant.